Activation of phosphatidylinositol 3’-kinase and its downstream mediator, Akt, promotes cellular survival and induces malignant transformation. Previous studies have reported loss of the PTEN lipid phosphatase, a negative regulator of AKT, and increased Ser473-phosphorylation of AKT in non-small cell lung cancer (NSCLC) biopsy samples and cell lines. Further, AKT phosphorylation is increased in biopsy samples of bronchial premalignancy, raising the possibility that AKT activation contributes to early stages of lung tumorigenesis. We investigated the role of this pathway in lung tumorigenesis by two creating mouse models: one with conditional PTEN loss and the other with over-expression of an activated form of AKT (gag-AKT). For the conditional PTEN model, PTEN was deleted by Cre-mediated recombination. Cre was expressed under the control of a bronchial epithelial-specific gene promoter (clara cell secretory protein or CCSP). By 3 months of age, PTEN deletion resulted in bronchial epithelial hyperplasia. Immunohistochemical analysis revealed increased Ser473 phosphorylation of Akt in hyperplastic regions. For the gag-AKT model, expression of the gag-AKT transgene was induced by the mifepristone regulator GLp65, which was under the control of a type II alveolar cell-specific gene promoter (surfactant protein C or SP-C). Preliminary studies have shown that mefipristone treatment induced gag-AKT expression in the alveolar epithelium. Studies are ongoing in both models to examine the tumorigenicity of these oncogenic signals in the lung.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]